The life expectancy of the world population has increased tremendously during the last 50 years. Our population is living longer than ever. The next ten years, it has been forecasted that there will be more people over 60 years of age than less than twenty years of age in Europe. More people will need medical help for diseases related to age, which will increase the pressure of the hospitals.
Bone is the second most common material to be transplanted after blood. The most reliable method to repair bone defects is to use autogenous bone, i.e. bone taken from another site in the body. However, problems may occur at the second surgical site where the graft is taken. To avoid this extra trauma allografts can be used, i.e. bone graft between individuals of the same species. Allografts have a lower osteogenic capacity than autografts and the rate of new bone formation might be lower. They also have a higher resorption rate, a larger immunogenic response and less revascularisation of the recipient. Allografts must also be controlled for viruses since they can transfer, for example, HIV and hepatitis. The use of allografts is now the most common method for bone transplantation and repairing of bone defects.
To solve the problems of supply, unpredictable strength and risk of infection, synthetic bone substitutes have become a realistic alternative. Thus, the demand for and use of synthetic bone substitutes is increasing rapidly.
Calcium sulfate hemihydrate, CaSO4½H2O, was one of the first materials investigated as a substitute for bone grafts. Studies have been undertaken since 1892 to demonstrate its acceptance by the tissues and rapid rate of resorption. It has been concluded that calcium sulfate hemihydrate implanted in areas of subcortical bone produces no further untoward reaction in the tissue than normally is present in a fracture. The new bone growing into calcium sulfate hemihydrate is normal bone. No side effects attributable to the implantation of calcium sulfate hemihydrate have been noted in adjacent tissues or in distant organs.
The most important advantage with calcium sulfate is its excellent biocompatibility. The drawbacks are the rapid resorbtion and low strength, which makes it less useful in larger or non-contained defects and when the fracture healing exceeds 4-6 weeks.
The dissolution rate of calcium sulfate has made it suitable as a carrier for drug release. In U.S. Pat. No. 5,614,206 pellets of calcium sulfate hemihydrate are shown, which are useful for controlled delivery of drugs. On implantation of a human or other animal, the pellets provide sustained and controlled delivery to a local site for periods ranging from 25 to 45 days.
Calcium phosphates, on the other hand, are suitable as bone substitutes because of their bioactive properties, i.e. having an effect on or obtaining response from living tissue. Their resorbtion rate is relatively slow, up to several years.
There are two different categories of calcium phosphates: CaP obtained by precipitation from an aqueous solution at room temperature (low-temperature CaP) and CaP obtained by a thermal treatment (high-temperature CaP).
Hydroxyapatite (HA) is the most stable calcium phosphate and the primary non-organic component of bone. Most of the bone graft substitutes on the market are made of hydroxyapatite. High temperature treated hydroxyapatite is highly crystalline and the least soluble of the calcium phosphates.
Hydroxyapatite and tri-calcium phosphate are the most common calcium phosphates used to fill bone defects and as implant coatings. Their resorbtion rate is relatively slow, from six months to several years. It is possible to increase the rate of degradation slightly by increasing the surface area of the material, decreasing the crystallinity and the crystal perfection and decreasing the size of crystals and grains in the material. A higher resorbtion rate can be preferable to encourage bone formation.
However, the biological characteristics and the anatomic site of implantation are also important for the behavior and outcome of the implant. The success of a biomaterial in one specific application does not guarantee its universal acceptance.
Bone mineral substitute materials can be prepared as a paste which can be injected directly into a fracture site. The paste is injected into the void in the bone and, upon hardening, an implant is obtained which conforms to the contours of the gap and supports the cancellous bone. Both calcium sulfate and hydroxyapatite materials have been extensively investigated as a possible alternative to autogenous bone grafts to help restore osseous defects of bone and fixation of bone fracture.
In this connection it is important that a complete stability is obtained as quickly as possible during or after surgery in order to prevent motions at site of healing. This especially applies to fractures, but also when filling of a bone cavity or replacing bone lost during tumor removal the healing is inhibited by movements and the in-growth of new bone is prevented. Thus, the injected material must cure fast and adhere firmly to the bone tissue.
However, during or after surgery complications, such as infections, can arise. Cavities may also be previously infected and have to be treated with for example antibiotics.
It is also of importance that the hardened material is so similar in structure to the bone so that it can be gradually resorbed by osteoclasts and replaced by new bone. This process can be facilitated if the hardened cement is provided with pores, which can transport nutrients and provide vascular ingrowth allowing new bone formation.
M. Bohner et al. disclosed at the Sixth World Biomaterials Congress Transactions (15-20/5 2000) a method to obtain an open macroporous calcium phosphate block by using an emulsion of a hydrophobic lipid (oil) in an aqueous calcium phosphate cement paste or an emulsion of an aqueous calcium phosphate cement paste in oil. After setting, the cement block was sintered at 1250° C. for 4 hours. Likewise, CN 1193614 shows a porous calcium phosphate bone cement for repairing human hard tissue. The cement contains pore-forming agent which may be a non-toxic surfactant, or a nontoxic slightly soluble salt, acidic salt and alkaline salt.
However, a high temperature treatment (>1000° C.) is normally required in order to burn out the added substances. Thus, the emulsion technique cannot yet be used to make bone substitutes that set in vivo. Trials to mix mannitol and sucrose crystals with calcium phosphate have been performed in order to obtain biphasic bone substitute pastes, where one phase dissolves to provide porosity in the set material. Another technique to obtain pores is the addition of air-entraining agents that stabilize the air bubbles created in the paste during mixing, a porous set material thus being provided (Sarda et al., Bioceramics 2002; 218(2):335).
Studies have also been made on mixtures of the above mentioned bone mineral substitute materials. U.S. Pat. No. 4,619,655 discloses a bone mineral substitute material comprising a mixture of calcium sulfate hemihydrate and calcium phosphate ceramic particles, preferably composed of hydroxyapatite, or tricalcium phosphate or mixtures thereof. According to this document, the calcium sulfate hemihydrate was completely resorbed within a few weeks and replaced by connective tissue when material composed of 50/50 mixtures of hydroxyapatite/calcium sulfate hemihydrate were implanted into experimentally created defects in rat mandible. The hydroxyapatite was not resorbed and some particles were eventually completely surrounded by bone. It was therefore concluded that the calcium sulfate hemihydrate acted as filler and scaffold for the incorporation of hydroxyapatite into bone.
A study presented on the “Combined Orthopaedic Research Societies Meeting”, Sept. 28-30, 1998, Hamamatsu, Japan, also shows additional tests relating to mixtures of calcium sulfate hemihydrate and hydroxyapatite. According to this study a combination of hydroxyapatite particles and calcium sulfate hemihydrate had a viscosity which allowed an easy placement of the implant material and prevented migration of hydroxyapatite particles into surrounding tissues during and after implantation. The experiments showed that calcium sulfate hemihydrate was absorbed in relatively short time, was easily manipulated with hydroxyapatite particles, and did not interfere with the process of bone healing.
WO 9100252 shows a composition which is capable of hardening in blood within about 10-45 min. The composition comprises essentially calcium sulfate hemihydrate with small amounts of calcium sulfate dihydrate. Organic and inorganic materials, such as hydroxyapatite, can also be included in the composition. After hardening, particles of hydroxyapatite are obtained within a calcium sulfate cement. The calcium sulfate cement is dissolved rapidly by aqueous body fluids within four weeks, leaving solid particles of hydroxyapatite.
Likewise, such particles of hydroxyapatite within a calcium sulfate cement are obtained by means of the method shown in WO 9117722. The composition for use as an animal implant comprises calcium sulfate hemihydrate, calcium phosphate, and sodium sulfate. The calcium phosphate is hydroxyapatite and the sodium sulfate enables the composition to be used in the presence of blood or other body fluids.
In WO 200205861 an injectable composition is shown, which is useful for a bone mineral substitute material. The dry powder of the composition comprises calcium sulfate hemihydrate, calcium phosphate and at least one accelerator. In contact with an aqueous liquid the composition will harden during surgery with accompanying early control of fracture fragment movement. A stable lasting implant is provided, which has a higher mechanical strength than trabecular bone, and the implant obtains with time a porous as well as irregular structure for bone in growth.